This invention relates to a composition and methods for treating hypertension. More particularly, the invention relates to a compound purified from a water extract of Palo de Brazil (Caesalpinia brasiliensis), methods of making, and methods of using for treating hypertension.
Blood pressure is measured as systolic (pressure of the blood in the arteries when the heart beats) and diastolic (pressure between heartbeats). High blood pressure, or hypertension, is generally considered to be a pressure greater than or equal to 140 systolic and 90 diastolic (measured in millimeters of mercury). High blood pressure is a serious but modifiable risk factor for heart disease and stroke.
High blood pressure occurs when the body""s smaller blood vessels (known as the arterioles) narrow, which causes the blood to exert excessive pressure against the vessel walls. The heart must therefore work harder to maintain this higher pressure. Although the body can tolerate increased blood pressure for months and even years, eventually the heart can enlarge and be damaged (a condition called hypertrophy), and injury to blood vessels in the kidneys, the brain, and the eyes can occur. Hypertension has been aptly called a silent killer, because it usually produces no symptoms.
Hypertension is referred to as essential, or primary, when the physician is unable to identify a specific cause. This is by far the most common type of high blood pressure, occurring in up to 95% of patients. Genetic factors appear to play a major role in essential hypertension. Several genetic factors, however, are probably involved that regulate important physiologic processes and interact with environmental influences to produce essential high blood pressure. Experts appear to have located the chromosomes (13 and 18) that house the genes responsible for blood pressure regulation, although pinning down the range of specific genes involved in hypertension is more difficult.
Secondary hypertension has recognizable causes, which are usually treatable or reversible. Causes of secondary hypertension include certain medical conditions, medications, alcohol, caffeine, and smoking. Medical conditions that contribute to temporary hypertension are pregnancy, cirrhosis, kidney disease, and Cushing""s disease. Certain prescription and over-the-counter drugs can cause temporary high blood pressure. Some prescription medications include cortisone, prednisone, estrogen, and indomethacin. Long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage and can also interfere with treatments for hypertension, including diuretics and beta-blockers. Such drugs include aspirin, ibuprofen (Advil, Motrin, Rufen), indomethacin (Indocin), naproxen (Anaprox, Naprosyn, Aleve), and many others. Of these drugs, aspirin appears to have the least detrimental effect on blood pressure. Cold medicines containing pseudoephedrine have also been found to increase blood pressure in hypertensive people, although they appear to pose no danger for those with normal blood pressure. High blood pressure is known to be an uncommon side effect in a few women taking oral contraceptives. Cocaine is known to cause acute episodes of hypertension, although apparently not chronic hypertension. An estimated 10% of hypertension cases are caused by alcohol abusexe2x80x94three alcoholic drinks a day or more. Caffeine causes a temporary increase in blood pressure, which has been thought to be harmless in people with normal blood pressure. One study, however, suggested that long term and regular coffee drinking can boost blood pressure sufficiently to increase the risk for heart disease in healthy men. The dangers of caffeine on blood pressure, however, pale next to the risks from smoking. One study reported that smokers have blood pressures up to 10 points higher than nonsmokers. Although cigar smoking does not appear to cause coronary artery disease, it can double the risk of death from cardiomyopathy and hypertension. Temporary high blood pressure can also result from stress, exercise, and long-term consumption of large amounts of licorice. Exposure to even low lead levels also appears to cause hypertension in adults. One small study showed that mobile phone use triggers a temporary rise in blood pressure, which may be harmful in people with existing hypertension.
Only 27% of American adults with high blood pressure have it under control; about the same percentage is on medications but not controlling their blood pressure, and nearly 15% of those with hypertension are not on medication at all. Aggressive drug treatment of long-term high blood pressure can significantly reduce the incidence of death from heart disease and other causes in both men and women. In people with diabetes, controlling both blood pressure and blood glucose levels prevents serious complications of that disease. If patients have mild hypertension and no heart problems, then lifestyle changes may suffice if carried out with determination. For more severe hypertension or for mild cases that do not respond to changes in diet and lifestyle within a year, drug treatment is usually necessary. A single-drug regimen can often control mild to moderate hypertension. More severe hypertension often requires a combination of two or more drugs.
Dozens of antihypertensive drugs are available. They usually fall into the categories of diuretics, which cause the body to excrete water and salt; ACE inhibitors, which reduce the production of angiotensin, a chemical that causes arteries to constrict; beta-blockers, which block the effects of adrenaline, thus easing the heart""s pumping action and widening blood vessels; vasodilators, which expand blood vessels; and calcium channel blockers, which help decrease the contractions of the heart and widen blood vessels. Research now indicates that beta-blockers, diuretics, and ACE inhibitors all reduce the risk for fatal and nonfatal cardiovascular events. As first-line treatment experts generally recommend beta-blockers or diuretics, which are inexpensive, safe, and effective, for most people with hypertension who have no complicating problems. Certain individuals, however, may have special requirements that call for specific drugs or combinations. All drugs used for hypertension have side effects, some distressing, and on-going compliance is difficult.
Plants have provided mankind with a valuable resource of unique and novel chemical compounds that have shown a wide variety of biological activities and have been used to treat a myriad of ailments. Ethnobotanical sources, such as modern and ancient herbals or carefully conducted interviews with indigenous healers and native shaman, have proven to be very effective means of identifying those plants of greatest medicinal importance. Some representative compounds discovered using documented ethnobotanical methodology include digitoxin (cardiac anti-arrhythmetic), turbocurarine (muscle relaxant), quinine (anti-malarial), and morphine (analgesic).
Surprisingly, 25% of all the prescription drugs in the United States in 1982 were extracted from plants. N. R. Farnsworth et al., 39 Econ. Bot. 231 (1985). In addition, over half of the current prescription drugs used in the United States are modeled after bioactive compounds originally found in plants. Id. Today, 80% of the world""s population still relies solely on plants for medication. M. J. Balick and P. A. Cox, Plants, People, and Culture (Scientific American Library, New York, N.Y., 1996). Public awareness of the medicinal value of natural products is evidenced by the fact that the last ten years has seen an explosive growth in the sale of herbal products in the United States as over-the-counter nutritional supplements.
Furthermore, advancements in synthetic organic chemistry have made it possible to synthesize not only newly identified natural products, but also structural analogs and semi-synthetic derivatives. It was not until the beginning of the twentieth century that organic chemistry had developed sufficiently to make synthetic drugs widely available. One of the first, and most notable, of these compounds was aspirin, acetylsalicylic acid, synthesized in 1899. E. S. Ayensu et al., Our Green and Living World (Smithsonian Institute Press, Washington, D.C., 1984). This synthetic compound was based on salicylates isolated from willow bark. G. Weissman, Scientific American 84 (January 1991). Today, it is estimated that Americans consume 16,000 tons of aspirin each year. Since 1899, synthetic natural products along with numerous analogs have resulted in many prescription medications, some with enhanced bioactivity over the natural product. Even with all the advances in synthetic organic chemistry, however, much time and effort is saved by using a model compound established through the elucidation of a novel natural product.
Isolation of natural products has now expanded to include marine organisms (primarily snails and sponges), fungi, bacteria, insects, and arthropods, and the number of newly reported compounds is growing rapidly. Although a number of plants have been well characterized, the plant kingdom still presents an essentially untouched reservoir of compounds of unparalleled structural diversity. Of the 250,000 to 750,000 plant species estimated to exist, only 0.01% of these have been exhaustively studied for biological activity. M. J. Balick and P. A. Cox, supra.
Traditional ethnobotanical sources are an effective means of finding, isolating, and identifying previously unknown biological compounds. Knowledgeable healers are often able to provide the common name and location of a local plant, a supply of plant tissue, extraction procedures, dosage levels, and diseases that can be effectively treated. This information helps to promote efficient identification of the bioactive component.
In view of the foregoing, it will be appreciated that providing a new antihypertensive drug and methods of use and making thereof would be significant advancements in the art.
It is an object of the present invention to provide a composition useful for treating high blood pressure.
It is another object of the invention to provide a method of isolating such an antihypertensive composition.
It is a further object of the invention to provide a method of making such an antihypertensive composition.
It is still another object of the invention to provide a method of treating hypertension.
These and other objects can be addressed by providing a purified compound having the formula: 
A method for isolating a compound having the formula: 
comprises:
(a) obtaining an aqueous leachate from Caesalpinia brasiliensis; 
(b) fractionating the leachate by reverse-phase high performance liquid chromatography; and
(c) selecting a fraction substantially free of haematoxylin and having an activity for reducing blood pressure in hypertensive Sprague-Dawley rats. Preferably, the aqueous leachate is from heartwood of Caesalpinia brasiliensis. 
A method for treating hypertension comprises administering an effective amount of a purified compound having the formula: 
Another aspect of the present invention relates to a composition comprising an admixture of an effective amount of a purified compound represented by the formula: 
and a pharmaceutically acceptable carrier.